Microneedle Tips Research Articles

Petromyzontidae‐Biomimetic Multimodal Microneedles‐Integrated Bioelectronic Catheters for Theranostic Endoscopic Surgery

AbstractCurrent catheter devices in minimally invasive surgery still possess limited functional options, lacking multimodal integration of both sensing and therapy. Catheter devices usually operate outside the tissue, incapable to detect intra‐tissue biochemical information for accurate localization and assessment of lesions during surgery. Inspired by the feature and functions of Petromyzontidae, here a multimodal core‐shell microneedles‐integrated bioelectronic catheter (MNIBC) for tissue‐penetrating theranostics in endoscopic surgery is developed. The microneedle (MN) device possesses individually addressable functionality at single‐MN tip resolution, enabling multiplex functions (a total of 11 functions distributed in three types of catheters) including biochemical sensing, myoelectric modulation, electroporation, and drug delivery in a submucosal environment. The MNIBC is prepared through hybrid fabrication and dimensionality reduction strategies, where the MN electrodes are functionalized with an MXene‐carbon nanotube (MXene‐CNT)‐based electron mediator, addressing the challenge of reduced electrode sensitivity on ultra‐small MN tip. The functionalities of MNIBC are demonstrated both ex vivo and in vivo on anesthetized rabbits via laparoscopy, simulated cystoscopy, and laparotomy. The MNIBC can effectively detect intra‐tissue biochemical signals in the bladder, and offers localized electroporation and intra‐tissue drug delivery for precise treatments of lesions. The versatile features of the MNIBC present a highly advanced platform for precise surgeries.

Safety and effectiveness of nano-pulse stimulation™ technology to treat acne vulgaris of the back.

This feasibility study describes the effects of Nano-pulse stimulation™ (NPS™) technology using the CellFX™ System on acne vulgaris of the back with the objectives of demonstrating safety and effectiveness. The CellFX System applies nanosecond pulses of electrical energy to induce highly localized regulated cell death (RCD) in the cellular structures of the targeted zone with no thermal effect on the tissue and negligible effects on surrounding non-cellular components. Seventeen subjects were enrolled at two sites with thirteen subjects completing treatment. Three 7 X 7 cm regions containing at least five bacne lesions each were identified, one region treated with the CellFX across three treatment sessions, the second region treated as a sham using microneedle tip placement without delivering energy, and the third as an untreated control. CellFX-treated areas showed an average reduction of acne lesions of 82% by 90 days post-last procedure. Acne improvement was observed in 100% of CellFX-treated regions compared to 39% improvement in Sham regions and 31% improvement in the control regions. The most common skin effects were erythema and hyperpigmentation observed in 23% and 92% of the subjects, respectively, at the last timepoint. No serious adverse events were reported. CellFX is a safe and effective procedure for clearing back acne.

Tofacitinib combined with melanocyte protector α-MSH to treat vitiligo through dextran based hydrogel microneedles

Vitiligo can cause serious damage to the appearance of patients and affect physical and mental health, but there is currently no simple and effective treatment. According to the theory of autoimmune disorder, the separable hydrogel microneedles delivering alpha-melanocyte-stimulating hormone (α-MSH) and tofacitinib were designed to treat vitiligo. This hydrogel microneedles were formed by dextran methacrylate (DexMA) and cyclodextrin-adamantane based host-guest supramolecules (HGSM) through CC double bond polymerization and host-guest assembly. The microneedle tips formed by the double cross-linked hydrogel can pierce the stratum corneum and deliver melanocyte protector α-MSH and JAK inhibitor tofacitinib directly to the epidermis and dermis. Under the treatment of α-MSH/tofacitinib microneedles, massive deposition of melanin in epidermis and hair follicles significantly accelerated skin and hair pigmentation.

Efficient fabrication of thermo-stable dissolving microneedle arrays for intradermal delivery of influenza whole inactivated virus vaccine.

Dissolving microneedle arrays (dMNAs) can be used to deliver vaccines via the intradermal route. Fabrication of dMNAs using centrifugation is the most common preparation method of dMNAs, but it results in a substantial loss of antigens. In order to solve the issue of antigen waste, we engineered an automatic dispensing system for dMNA preparation. Here, we report on the fabrication of influenza whole inactivated virus (WIV) vaccine-loaded dMNAs (WIV dMNAs) by using the automatic dispensing system. Prior to the dispensing process, polydimethylsiloxane (PDMS) moulds were treated with oxygen plasma to increase surface hydrophilicity. WIV dMNAs were prepared with 1% (w/v) trehalose and pullulan (50 : 50 weight ratio). During the dispensing process, reduced pressure was applied to the PDMS mould via a vacuum chamber to make microneedle cavities airless. After producing dMNAs, WIV was quantified and 1.9 μg of WIV was loaded per dMNA, of which 1.3 μg was in the microneedle tips. Compared to the centrifugation method, this automatic dispensing system resulted in a 95% reduction of antigen waste. A hemagglutination assay confirmed that WIV dMNA maintained the stability of the antigen for at least four weeks of storage, even at room temperature or at 37 °C. The WIV dMNAs displayed 100% penetration efficiency in human skin, and 83% of the microneedle volume was dissolved in the skin within 10 minutes. In a vaccination study, mice immunised with WIV dMNAs showed similar IgG levels to those that received WIV intramuscularly. In conclusion, using the automatic dispensing system for dMNA production strongly reduced antigen waste and yielded dMNAs with excellent physical, mechanical, and immunological properties.

A transdermal drug delivery system based on dissolving microneedles for boron neutron capture therapy of melanoma.

Boron neutron capture therapy (BNCT) is a promising therapy for malignant tumors that requires selective and high concentrations of 10B accumulation in tumor cells. Despite ongoing developments in novel boron agents and delivery carriers, the progress and clinical application of BNCT is still restricted by the low 10B accumulation and tumor-to-normal tissue (T/N) ratio. Herein, a dissolving microneedle-based transdermal drug delivery system was specifically designed for BNCT in a mouse model of melanoma. By incorporating fructose-BPA (F-BPA) into PVA microneedle tips, this system successfully delivered sufficient F-BPA into the melanoma site after the application of only two patches. Notably, the T/N ratio achieved through the treatment combining PVA/F-BPA MNs with BNCT (PVA/F-BPA MNs-BNCT) surpassed 93.16, signifying a great improvement. Furthermore, this treatment approach effectively inhibited tumor growth and significantly enhanced the survival rate of the mice. In brief, our study introduces a novel, simple, and efficient administration strategy for BNCT, opening new possibilities for the design of nanomedicine for BNCT.

Dissolvable polymeric microneedles loaded with aspirin for antiplatelet aggregation

To reduce mucosal damage in the gastrointestinal tract caused by aspirin, we developed a dissolvable polymeric microneedle (MN) patch loaded with aspirin. Biodegradable polymers provide mechanical strength to the MNs. The MN tips punctured the cuticle of the skin and dissolved when in contact with the subcutaneous tissue. The aspirin in the MN patch is delivered continuously through an array of micropores created by the punctures, providing a stable plasma concentration of aspirin. The factors affecting the stability of aspirin during MNs fabrication were comprehensively analyzed, and the hydrolysis rate of aspirin in the MNs was less than 2%. Compared to oral administration, MN administration not only had a smoother plasma concentration curve but also resulted in a lower effective dose of antiplatelet aggregation. Aspirin-loaded MNs were mildly irritating to the skin, causing only slight erythema on the skin and recovery within 24 h. In summary, aspirin-loaded MNs provide a new method to reduce gastrointestinal adverse effects in patients requiring aspirin regularly.

Bee Sting-Inspired Inflammation-Responsive Microneedles for Periodontal Disease Treatment.

Periodontal lesions are common and frustrating diseases that impact life quality. Efforts in this aspect aim at developing local drug delivery systems with better efficacy and less toxicity. Herein, inspired by the sting separation behavior of bees, we conduct novel reactive oxygen species (ROS)-responsive detachable microneedles (MNs) that carry antibiotic metronidazole (Met) for controllable periodontal drug delivery and periodontitis treatment. Benefiting from the needle-base separation ability, such MNs can penetrate through the healthy gingival to reach the gingival sulcus's bottom while offering minimal impact to oral function. Besides, as the drug-encapsulated cores were protected by poly (lactic-co-glycolic acid) (PLGA) shells in MNs, the surrounding normal gingival tissue is not affected by Met, resulting in excellent local biosafety. Additionally, with the ROS-responsive PLGA-thioketal-polyethylene glycol MN tips, they can be unlocked to release Met directly around the pathogen under the high ROS in the periodontitis sulcus, bringing about improved therapeutic effects. Based on these characteristics, the proposed bioinspired MNs show good therapeutic results in treating a rat model with periodontitis, implying their potential in periodontal disease.

Antibacterial, adhesive, and MSC exosomes encapsulated microneedles with spatio-temporal variation functions for diabetic wound healing

Chronic wounds affect healthcare systems and increase the risk of infection. Despite the clinical demand for improving healing, an effective and safe therapeutic approach is still lacking. Here, we present a novel spatio-temporal-varying adhesive microneedle (MN) patch encapsulated with mesenchymal stem cell-derived exosomes (MSC-exos) and antibacterial Ag nanoparticles (AgNPs) for improving wound healing. This MN patch is fabricated by replicating a predesigned flexible template. Consisting of porous methacrylate gelatin hydrogels, the MN tips can continuously deliver anti-inflammatory and pro-angiogenic MSC-exos to wound beds, which can accelerate healing by improving cell functions, remodeling blood vessels and restoring immune systems. Besides, the silk-fibroin-composed MN back enables the patch to stick to the skin well and fix at the wounded site, thus avoiding secondary bandage. By incorporating AgNPs in the MN back, the MN patch is endowed with the ability to efficiently resist microbial contamination and further benefits wound repair. Such a composite MN patch performs well in relieving inflammation, promoting angiogenesis, and suppressing wound-infecting bacteria during wound injury in diabetic rats, with no adverse effects observed. All the features make this multifunctional MN patch potentially valuable for clinical applications.

Detachable Microneedle Patches Deliver Mesenchymal Stromal Cell Factor-Loaded Nanoparticles for Cardiac Repair.

Intramyocardial injection is a direct and efficient approach to deliver therapeutics to the heart. However, the injected volume must be very limited, and there is injury to the injection site and leakage issues during heart beating. Herein, we developed a detachable therapeutic microneedle (MN) patch, which is comprised of mesenchymal stromal cell-secreted factors (MSCF)-loaded poly(lactic-co-glycolic acid) nanoparticles (NP) in MN tips made of elastin-like polypeptide gel, with a resolvable non-cross-linked hyaluronic acid (HA) gel as the MN base. The tips can be firmly inserted into the infarcted myocardium after base removal, and no suture is needed. In isolated neonatal rat cardiac cells, we found that the cellular uptake of MSCF-NP in the cardiomyocytes was higher than in cardiac fibroblasts. MSCF-NP promoted the proliferation of injured cardiomyocytes. In a rat model of myocardial infarction, MN-MSCF-NP treatment reduced cardiomyocyte apoptosis, restored myocardium volume, and reduced fibrosis during the cardiac remodeling process. Our work demonstrated the therapeutic potential of MN to deliver MSCF directly into the myocardium and provides a promising treatment approach for cardiac diseases.

Geometric Characterization of Local Changes in Tungsten Microneedle Tips after In-Vivo Insertion into Peripheral Nerves

Peripheral neural interfaces are used to connect the peripheral nervous system to high-tech robotic devices and computer interfaces. Soft materials are nowadays used to build the main structural part of these interfaces because they are able to mimic the mechanical properties of peripheral nerves. However, if on the one hand soft materials provide effective connections, reducing mechanical mismatch with nervous tissues and creating a close contact between active sites and neural fibers, on the other hand, most of them are not mechanically stable during implantation. As a consequence, tungsten (W) microneedles are used to insert soft neural interfaces, because they are able to pierce the peripheral nervous tissue because of their high stiffness. Nevertheless, this stiffness cannot prevent microneedles from local microscopic structural damage, even after successful insertions. In addition, the nature of this damage is not totally clear. Therefore, this work aimed at quantitatively investigating the phenomenological changes of the microneedles’ tip shape after insertion into the in vivo peripheral nerves. In particular, a quantification of the interactions between peripheral nerves and W microneedles was proposed through the Oliver-Pharr formula, and the interaction force was found to be directly proportional to the power < m > = 2.124 of the normalized indentation depth. Moreover, an experimental correlation between insertion force and the opening tip angle was described together with an assessment of the minimum diameter to effectively puncture the peripheral nervous tissue. Finally, a computational framework was presented to describe the local changes affecting the microneedles’ tip shape. This approach was able to detect a bulging phenomenon along with the microneedle tips with a characteristic amplitude of approximately 100 μm, and a folding phenomenon, with a characteristic mean amplitude of less than 20 μm, affecting the extreme ending sections of the microneedle tips. These geometrical changes were related to the synergistic action of interaction forces likely resulting in compression and elastic instability of the tip.

Intradermal Glycine Detection with a Wearable Microneedle Biosensor: The First In Vivo Assay.

Glycine (GLY) is gaining importance in medical diagnoses due to its relationship with multiple physiological functions. Today, GLY is exclusively analyzed using instrumentation centralized in clinical labs, and a tangible point-of-care tool that gathers real-time data from the patient for effective and fast evaluations is lacking. Relevant clinical advances are expected as soon as the rapid provision of both punctual and continuous measurements is possible. In that context, this work presents a microneedle (MN)-based biosensor for intradermal GLY detection in interstitial fluid (ISF). The MN tip is externally tailored to detect GLY levels through the hydrogen peroxide formed in its reaction with a quinoprotein-based GLY oxidase enzyme. The analytical performance of the MN biosensor indicates a fast response time (<7 s); acceptable reversibility, reproducibility, and stability; as well as a wide linear range of response (25-600 μM) that covers the physiological levels of GLY in ISF. The MN biosensor conveniently exhibits high selectivity for GLY over other compounds commonly found in ISF, and the response is not influenced by temperature, pH, or skin insertions. Validated intradermal measurements of GLY were obtained at the in vitro (with pieces of rat skin), ex vivo (on-body tests of euthanized rats) and in vivo (on-body tests of anesthetized rats) levels, demonstrating its ability to produce accurate physiological data. The developed GLY MN biosensor is skin-wearable and provides reliable, real-time intradermal GLY measurements in ISF by means of a minimally invasive approach.

Effect of Surface Interactions on Microsphere Loading in Dissolving Microneedle Patches.

Microneedle (MN) patches enable simple self-administration of drugs via the skin. In this study, we sought to deliver drug-loaded microspheres (MSs) using MN patches and found that the poly(lactic-co-glycolic acid) (PLGA) MSs failed to localize in the MN tips during fabrication, thereby decreasing their delivered dose and delivery efficiency into skin. We determined that surface interactions between the hydrophobic MSs and the poly(dimethylsiloxane) (PDMS) mold caused MSs to adhere to the mold surface during casting in aqueous formulations, with hydrophobic interactions largely responsible for adhesion. Further studies with polystyrene MSs that similarly carry a negative charge like the PLGA MSs demonstrated both repulsive electrostatic interactions as well as adhesive hydrophobic interactions. Reducing hydrophobic interactions by addition of a surfactant or modifying mold surface properties increased MS loading into MN tips and delivery into porcine skin ex vivo by 3-fold. We conclude that surface interactions affect the loading of hydrophobic MSs into MN patches during aqueous fabrication procedures and that their modulation with the surfactant can increase loading and delivery efficiency.

Fabrication and characterization of innovative chitosan/doxorubicin coated3Dprinted microneedle patch for prolonged drug delivery

AbstractIn this study, microneedles (MNs) were successfully fabricated using the 3D printing method, which provides ease of production and reproduction in the desired size. Chi/Dox MNs drug delivery systems containing doxorubicin (Dox) were successfully produced in the presence of glutaraldehyde, which was coated with chitosan (Chi) and used as a crosslinker to prolong the drug release of the produced MNs. The obtained Chi/Dox MNs drug distribution systems were characterized by SEM, FTIR, zeta, contact angle, surface energy, compression test, and drug release tests. With the SEM analyzes performed before and after coating, it was observed that the MNs were in micro dimensions, and the diameters of the MNs tips before and after coating were 41.22 μm and 54.58 μm, respectively. After the compression test, it was analyzed that each MNs could withstand a force of about 76 N. The zeta potentials of Chi and Dox solutions were measured as 8.8 and 21.5 mV, respectively. FTIR, zeta potential, contact angle, and surface energy results confirm the Dox coating and their interactions. It has been observed that Chi/Dox MNs has successfully extended drug release time without drug‐burst, and their use in skin cancer treatment is promising.

Numerical Simulation, Analysis, and Fabrication of MEMS-Based Solid Ag and Cu Microneedles for Biomedical Applications

Microelectromechanical system (MEMS)-based devices have gained attention recently due to their beneficial biomedical applications. MEMS-based devices like microneedles have set new trends in drug delivery, vaccination, skin, and eye treatment. Different materials like metals, sugars, polymers, and silicon have been used for fabrication. Various techniques have been used for their fabrication, including laser ablation, lithography, injection molding, and additive manufacturing. The tip diameter of different micron ranges has been achieved. The strength and stiffness of the microneedle’s tip have always been important in fabricating microneedles so that it does not break on insertion. This research paper presents a comparison between silver (Ag) and copper (Cu) solid microneedles by performing numerical analysis using the fuzzy approach, structural simulation, and fabrication. Firstly, structural simulation has been performed in ANSYS software to test the strength of silver (Ag) and copper (Cu) microneedles separately. The purpose is to compare the stress effect and fracture limit of both microneedles. The results collected from the simulation provide valuable target and prediction facts to fabricate improved designs of the solid Ag and Cu microneedles. Then, fuzzy-based numerical analysis has been performed in MATLAB software for both microneedles separately. In this numerical analysis, the effect on the range of microneedle tip diameter and cone length has been observed by varying input voltage and time. Finally, fabrication has been performed using a novel economical technique such as electrochemical etching. Electrochemical etching is a very low-cost and clean room-free technique as compared to other techniques used for the fabrication of microneedles. The fabrication technique adopted in this work is the same for both silver and copper microneedles. The scanning electron microscopy (SEM) characterization has been performed for both fabricated microneedle tips. The tip of the fabricated solid Ag and Cu microneedle has been then coated with drugs using the dip-coating method. The coated solid Ag and Cu microneedle’s tip has been then characterized again using SEM. The numerical results calculated from the fuzzy analysis have been then compared with fabrication results. The fuzzy analysis gives the simulated size of the microneedle’s tip for 5.05 μm silver and 5.12 μm copper which have very close approximation with the experimental values from the SEM micrographs which also give the values of the cone length from 400 to 500 μm and the tip size from 5 to 6 μm for the time of 10–15 minutes, whose values were optimized by the fuzzy analysis. The results of this research provide valuable benchmark and prediction data to fabricate improved designs of the silver solid microneedles for drug delivery and other biomedical applications.

Persistent Production of Reactive Oxygen Species with Zn2GeO4:Cu Nanorod-Loaded Microneedles for Methicillin-Resistant Staphylococcus Aureus Infectious Wound Healing.

Skin wound infection caused by methicillin-resistant Staphylococcus aureus (MRSA) is an urgent concern. Photodynamic therapy has emerged as a promising means of combating bacterial infection. However, continuous or repeated in situ light excitation is required for photosensitizers to produce reactive oxygen species (ROS), and most photosensitizers need sufficient oxygen to produce singlet oxygen (1O2), which greatly limits their clinical application. In this work, we report the preparation of Zn2GeO4:Cu2+ (ZGC) persistent luminescence nanorods with excellent ability for persistent ROS production after stopping excitation for MRSA infectious wound healing. The prepared ZGC nanorods were loaded into dissolvable microneedles (MNs) (ZGC@MNs) to penetrate biofilms and treat MRSA-infected wounds in a minimally invasive manner. ZGC showed a long-persistent photocatalytic effect to constantly produce multiple ROS (1O2, hydroxyl radical, and superoxide radical) accompanied by persistent luminescence after a pre-illumination. The MN tips of ZGC@MNs were rapidly dissolved to release ZGC for the continuous production of multiple ROS for at least 48 h with no need for in situ excitation and no special requirement on the amount of oxygen for eliminating MRSA biofilms. The developed ZGC@MN patches exhibited excellent antibacterial activity and biocompatibility for effectively reducing inflammation and promoting wound healing in vivo.

Low-Temperature Multiple Micro-Dispensing on Microneedles for Accurate Transcutaneous Smallpox Vaccination.

Smallpox is an acute contagious disease caused by the variola virus. According to WHO guidelines, the smallpox vaccine is administrated by scarification into the epidermis using a bifurcated needle moistened with a vaccine solution. However, this invasive vaccination method involving multiple skin punctures requires a special technique to inoculate, as well as a cold chain for storage and distribution of vaccine solutions containing a live virus. Here, we report a transcutaneous smallpox vaccination using a live vaccinia-coated microneedle (MN) patch prepared by a low-temperature multiple nanoliter-level dispensing system, enabling accurate transdermal delivery of live vaccines and maintenance of bioactivity. The live vaccinia in hyaluronic acid (HA) solutions was selectively coated on the solid MN tips, and the coating amount of the vaccine was precisely controlled through a programmed multiple dispensing process with high accuracy under low temperature conditions (2–8 °C) for smallpox vaccination. Inoculation of mice (BALB/C mouse) with the MN patch coated with the second-generation smallpox vaccine increased the neutralizing antibody titer and T cell immune response. Interestingly, the live vaccine-coated MN patch maintained viral titers at −20 °C for 4 weeks and elevated temperature (37 °C) for 1 week, highlighting improved storage stability of the live virus formulated into coated MN patches. This coated MN platform using contact dispensing technique provides a simple and effective method for smallpox vaccination.

Fabricating High-Resolution and High-Dimensional Microneedle Mold through the Resolution Improvement of Stereolithography 3D Printing

Microneedles are transdermal drug delivery tools that can be fabricated simply, economically, and rapidly using SLA 3D printing. However, SLA 3D printing has a limitation in that the resolution is slightly lowered when the microneedle is precisely printed. To solve this issue, we optimized the SLA 3D printing conditions such as printing angle, needle height, aspect ratio, and spacing between the microneedles for high-resolution microneedle fabrication. The sharpest microneedle tip was obtained when the printing angle was adjusted to 60° in both the x and y axes. The aspect ratio and the spacing between the microneedles did not affect the output of the sharp tip. Under optimal conditions, the microneedles with 1180 ± 20 µm height, 490 ± 20 µm base, and 30.2 ± 3.4 µm tip diameter were obtained. The dissolving microneedle patch, prepared using the 3D printed microneedle as a mold, penetrated the porcine skin ex vivo. When the printing angle was 60° in the x and y axes, the area of the single stacking layer, including the microneedle tip, increased, and thus the sharp tip could be printed. A high-dimensional, side-notched arrowhead (SNA) microneedle was fabricated by applying the SLA 3D printing condition. Moreover, a letter-type microneedle patch was fabricated using the customized characteristics of 3D printing. Consequently, high-resolution and high-dimensional microneedles were successfully fabricated by adjusting the printing angle using a general SLA 3D printer, and this technology will be applied to the manufacture of drug delivery tools and various microstructures.

Lamprey-Teeth-Inspired Oriented Antibacterial Sericin Microneedles for Infected Wound Healing Improvement.

The therapeutic efficacy of wound infections caused by bacteria is challenged by limited wound repairs and a high risk of inflammation. Microneedles have been generated for wound healing since they are able to efficiently pierce the epidermis and deliver drugs. However, regular microneedles cannot provide oriented traction to "shrink" the wound area, and most microneedles are made of inert polymers, which mainly serve as a support but rarely participate in the following physiological processes. Herein, inspired by lamprey teeth, we designed oriented antibacterial sericin microneedles with dually functionalized needles to provide penetration and directional traction. Sericin, derived from silkworm cocoons, was employed to fabricate microneedle tips, significantly improving skin repair via hair follicle regeneration and angiogenesis. Besides, zinc oxide nanoparticles were integrated as an antibacterial module, endowing the OASM with high bacterial suppression. It is believed that the synergy of these systems may effectively heal infected wounds, suggesting its clinically translational potential.

Self-Powered Electrical Impulse Chemotherapy for Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a common oral cancer of the head and neck, which causes tremendous physical and mental pain to people. Traditional chemotherapy usually results in drug resistance and side effects, affecting the therapy process. In this study, a self-powered electrical impulse chemotherapy (EIC) method based on a portable triboelectric nanogenerator (TENG) was established for OSCC therapy. A common chemotherapeutic drug, doxorubicin (DOX), was used in the experiment. The TENG designed with zigzag structure had a small size of 6 cm × 6 cm, which could controllably generate the fixed output of 200 V, 400 V and 600 V. The electrical impulses generated by the TENG increased the cell endocytosis of DOX remarkably. Besides, a simply and ingeniously designed microneedle electrode increased the intensity of electric field (EF) between two adjacent microneedle tips compared with the most used planar interdigital electrode at the same height, which was more suitable for three-dimensional (3D) cells or tissues. Based on the TENG, microneedle electrode and DOX, the self-powered EIC system demonstrated a maximal apoptotic cell ratio of 22.47% and a minimum relative 3D multicellular tumor sphere (MCTS) volume of 160% with the drug dosage of 1 μg mL−1.

Polydopamine Decorated Microneedles with Fe-MSC-Derived Nanovesicles Encapsulation for Wound Healing.

Wound dressing with the capacities of antioxidation, antiinflammation, and efficient angiogenesis induction is expected for effectively promoting wound healing. Herein, a novel core‐shell hyaluronic acid (HA) microneedle (MN) patch with ferrum‐mesenchymal stem cell‐derived artificial nanovesicles (Fe‐MSC‐NVs) and polydopamine nanoparticles (PDA NPs) encapsulated in the needle tips is presented for wound healing. Fe‐MSC‐NVs containing multifunctional therapeutic cytokines are encapsulated in the inner HA core of the MN tips for accelerating angiogenesis. The PDA NPs are encapsulated in the outer methacrylated hyaluronic acid (HAMA) shell of the MN tips to overcome the adverse impacts from reactive oxygen species (ROS)‐derived oxidative stress. With the gradual degradation of HAMA patch tips in the skin, the PDA NPs are sustainably released at the lesion to suppress the ROS‐induced inflammation reaction, while the Fe‐MSC‐NVs significantly increase the migration, proliferation, and tube formation of human umbilical vein endothelial cells (HUVEC). More attractively, the combination of PDA NPs and Fe‐MSC‐NVs further promotes M2 macrophage polarization, thereby suppressing wound inflammation. Through in vivo experiment, the Fe‐MSC‐NVs/PDA MN patch shows an excellent effect for diabetic wound healing. These features of antioxidation, antiinflammation, and pro‐angiogenesis indicate the proposed composite core‐shell MN patch is valuable for clinical wound healing applications.